Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry

Shiori Haga, Norio Yamamoto, Chikako Nakai-Murakami, Yoshiaki Osawa, Kenzo Tokunaga, Tetsutaro Sata, Naoki Yamamoto, Takehiko Sasazuki, Yukihito Ishizaka

Research output: Contribution to journalArticle

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Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a high-risk infectious pathogen. In the proposed model of respiratory failure, SARS-CoV down-regulates its receptor, angiotensin-converting enzyme 2 (ACE2), but the mechanism involved is unknown. We found that the spike protein of SARS-CoV (SARS-S) induced TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain. The modulation of TACE activity by SARS-S depended on the cytoplasmic domain of ACE2, because deletion mutants of ACE2 lacking the carboxyl-terminal region did not induce ACE2 shedding or TNF-α production. In contrast, the spike protein of HNL63-CoV (NL63-S), a CoV that uses ACE2 as a receptor and mainly induces the common cold, caused neither of these cellular responses. Intriguingly, viral infection, judged by real-time RT-PCR analysis of SARS-CoV mRNA expression, was significantly attenuated by deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression by siRNA. These data suggest that cellular signals triggered by the interaction of SARS-CoV with ACE2 are positively involved in viral entry but lead to tissue damage. These findings may lead to the development of anti-SARS-CoV agents.

Original languageEnglish
Pages (from-to)7809-7814
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number22
DOIs
Publication statusPublished - Jun 3 2008
Externally publishedYes

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Severe Acute Respiratory Syndrome
Coronavirus
Enzymes
Proteins
Common Cold
angiotensin converting enzyme 2
Virus Diseases
Respiratory Insufficiency
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Down-Regulation
Messenger RNA

All Science Journal Classification (ASJC) codes

  • General

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Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry. / Haga, Shiori; Yamamoto, Norio; Nakai-Murakami, Chikako; Osawa, Yoshiaki; Tokunaga, Kenzo; Sata, Tetsutaro; Yamamoto, Naoki; Sasazuki, Takehiko; Ishizaka, Yukihito.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 22, 03.06.2008, p. 7809-7814.

Research output: Contribution to journalArticle

Haga, Shiori ; Yamamoto, Norio ; Nakai-Murakami, Chikako ; Osawa, Yoshiaki ; Tokunaga, Kenzo ; Sata, Tetsutaro ; Yamamoto, Naoki ; Sasazuki, Takehiko ; Ishizaka, Yukihito. / Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 22. pp. 7809-7814.
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